Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production. The Th2 cell bias of Rasa3-deficient T cells was due to aberrantly elevated transcription factor IRF4 expression. RASA3 promoted proteasome-mediated IRF4 protein degradation by facilitating interaction of IRF4 with E3-ubiquitin ligase Cbl-b. Therefore, a RASA3-IRF4-Cbl-b pathway specifically directs pTh17 cell generation by balancing reciprocal Th17-Th2 cell programs. These findings indicate that a distinct molecular program directs pTh17 cell generation and reveals targets for treating pTh17 cell-related pathology and diseases.

致病性Th17（pTh17）细胞驱动炎症和免疫病理，但是pTh17细胞是否为Th17细胞亚群，其生成受特定分子控制，这一点尚待解决。我们发现Ras p21蛋白激活物3（RASA3）由pTh17细胞相对于非pTh17细胞高度表达，是体外和体内pTh17生成所特有的。在实验性自身免疫性脑脊髓炎期间，T细胞中有条件地缺乏Rasa3的小鼠表现出较少的病理。缺乏Rasa3的T细胞获得了Th2细胞偏向的程序，该程序主要通过白介素4的产生反式抑制pTh17细胞的产生。Rasa3的Th2细胞偏倚 缺陷性T细胞是由于转录因子IRF4表达异常升高所致。RASA3通过促进IRF4与E3-泛素连接酶Cbl-b的相互作用来促进蛋白酶体介导的IRF4蛋白降解。因此，RASA3-IRF4-Cbl-b途径通过平衡相互的Th17-Th2细胞程序来直接指导pTh17细胞的产生。这些发现表明，不同的分子程序指导pTh17细胞的生成，并揭示了治疗pTh17细胞相关的病理学和疾病的靶标。